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Pexelizumab: Complement inhibition for the cardiac patient?Kevin Ng, MD; Hong Liu, MD
Andrew Maslow, MD
Although inflammation is a normal response, continued exposure to foreign surfaces, toxic antigens, and tissue injury results in pathologic local and systemic inflammation (SIRS). 1-3 This response involves multiple humoral and cellular components, including the coagulation (Factor XII, thrombin, Proteins C and S, platelets) and complement systems, cytokines (TNF-alpha, interleukins), leukocytes, monocytes, adhesion molecules (ICAM-1), and endothelial cells, among others. 1-3 The complement system is a group of glycoproteins, which, when activated, results in the formation of C3-convertase, which converts C3 to C3a and C3b. C3a cleaves C5 to C5a and C5b. 3 C5b, in conjunction with C6, C7, C8, and C9, forms the membrane attack or terminal complement complex (TCC) C5b-9. Both C5a and C5b-9 activate, promote, and amplify inflammatory components, and likely play central roles in the development of SIRS, tissue injury, reperfusion injury, and apoptosis. An in-vivo rat model of myocardial ischemia has demonstrated that monoclonal antibody to C5 (18a) blocks conversion to C5a and C5b-9 and may prevent myocardial accumulation of leukocytes.4 This was associated with a 40% to 70% reduction in myocardial infarct size, with greater benefit seen when 18a was administered prior to ischemia than prior to reperfusion. Furthermore, expression of p21 (Ras), an initiator of apoptosis, was attenuated in animals receiving 18a. Pexelizumab (Alexion Pharmaceuticals), a recombinant humanized single chain monoclonal antibody to C5, blocks the conversion of C5 to C5a and C5b-9. In a clinical perioperative study, the pharmacokinetics of pexelizumab was assessed during hypothermic cardiopulmonary bypass (CPB). 5 The elimination half-life ranged from 7.0 hours to14.5 hours, the latter after a dose of 2.0 mg/kg. For patients receiving 2.0 mg/kg, serum complement activity was negligible from the time of administration to about two hours following exposure to CPB. Serum monocyte and leukocyte activities were also reduced for two to 12 hours after CPB. Despite earlier experimental benefit, two non-surgical investigations, COMMA (COMplement inhibition in Myocardial infarction treated with Angioplasty) and COMPLY (COMplement inhibition in myocardial infarction treated with thromboLYtics), reported no clinical impact on CPK-MB release nor electrocardiographic changes with the administration of pexelizumab.6,7 While the COMPLY study reported no difference in composite outcome (death, infarct, congestive heart failure, stroke),6 the COMMA trial reported a reduction in 90-day (5.9% versus 1.8%) and 180-day (7.4% versus 3.2%) mortality with pexelizumab treatment.7 However, the statistical analysis did not include other outcome predictors, nor did it confirm the authors' speculation that the clinical benefit was due to reduction in ventricular remodeling, apoptosis, and preservation of endothelial cell function.7 Neurocognitive outcome was assessed in a recent report involving patients undergoing cardiac surgery with pexelizumab (2.0 mg/kg bolus and infusion 0.05 mg/kg/hr).8 Overall neurocognitive outcome was not altered. However, analyses of individual domains showed fewer patients had a less than 10% reduction of baseline visual-spatial function in patients receiving pexelizumab at four (56% versus 40%; p=0.003) and 30 days (21% versus 12%; p=0.016) after surgery. Although not powered to detect differences in individual domains, these data represent a possible non-cardiac benefit of pexelizumab. Two other clinical investigations compared composite cardiac outcomes in patients randomized to pexelizumab (2 mg/kg; 0.05 mg/kg/hr) or placebo scheduled for coronary artery bypass grafting requiring CPB with or without heart valve surgery.9,10 There were no significant clinical outcome benefits of pexelizumab in the primary analyses, despite near complete suppression of C5a activity. In one study,9 a post-hoc analysis of 'coronary artery bypass grafting-alone' patients (n=800) revealed a greater CPK-MB release in the placebo group (50 ng/ml versus 30 ng/ml; p< 0.01).9 Further analysis reported a significant reduction in myocardial infarction (2.7% versus 7.8%; p=0.01) with pexelizumab. In the secondary analysis of the other study involving patients undergoing coronary artery bypass grafting with or without valve surgery (n=3099),10 a reduction in composite outcome (myocardial infarction, death) in the pexelizumab group was found at thirty days (11.0% versus 14.0%; p=0.03). When further analyzed, only non-Q wave myocardial infarctions were significantly reduced in the pexelizumab group. There was also a statistically insignificant increase in postoperative pneumonia in the pexelizumab group (1.2% versus 2.4%), while overall infectious burden was not different between groups. In these two studies, it is not clear that the post-hoc or secondary analyses included other outcome predictors or proper statistical corrections (Bonferroni). Furthermore, data such as ventricular and valvular function, CPB management, type of valve surgery, perioperative complications, and cause of death were not listed nor analyzed. Given the multiple components of the inflammatory response, therapy aimed at only one pathway may be insufficient to prevent injury. In an ex-vivo rat heart experiment, it was shown that pre-ischemic exposure to sevoflurane reduced the activity of nuclear factor (NF)-[Kappa]B, a nuclear transcription factor, which was associated with decreased myocardial inflammation and myocardial injury due to ischemia and reperfusion.11 In a similar experimental model, JTE-607, a cytokine inhibitor, prevented loss of CPK-MB, reduced various myocardial cytokines (TNF-alpha, IL-6, IL-8, and IL-1), and improved cardiac recovery after a thirty minute ischemic period.12 Finally, reduction of leukocytes using a leukocyte depleting filter placed in the CPB circuit was associated with shorter times to extubation, reduced intensive are unit and hospital stays, and improved respiratory function for patients with chronic obstructive lung disease.13 Other potential therapies, including serine protease inhibitors, antifibrinolytics, corticosteroids, and nonsteroidal anti-inflammatory medications, have demonstrated varying degrees of clinical efficacy. In summary, clinical investigations of anti-inflammatory therapies in patients undergoing cardiac surgery is an exciting, diverse, and dynamic field. Although pexelizumab is able to block C5 conversion, there is only preliminary evidence of real cardiac and non-cardiac benefits. While pexelizumab may eventually become part of a multimodal approach to limit pathologic perioperative inflammation, the cost of prophylactic therapy may be excessive. Alternative strategies need to be developed to identify patients at high risk for perioperative inflammation-related morbidity, so that expensive therapies can be applied most effectively. Alternatively, anti-inflammatory therapies could be potentially applied to treat systemic inflammation or reperfusion injury. However, this approach will probably be less effective 'once the cat is out of the bag'. Needless to say, this is an exciting area of clinical investigation that deserves watching, and will hopefully provide useful clinical strategies in the near future that truly affect outcome following cardiac surgery. References
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